Molecular sciences, such as chemistry, biophysics, molecular biology and protein science, are vital to innovations in medicine and the discovery of new medicines and diagnostics. As well as making a crucial contribution to health and society, industries in this field provide an essential component to the economy and contribute hugely to employment figures, currently generating nearly 500,000 jobs nationally. To enable and facilitate future economic growth in this area, the CDT will provide a cohort of researchers who have training in both aspects of this interface who will be equipped to become the future innovators and leaders in their field. All projects will be based in both molecular and medical sciences and will focus on unmet medical needs, such as understanding of disease biology, identification of new therapeutic targets, and new approaches to discovery and development of novel therapies. Specific problems will be identified by researchers within the CDT, industrial partners, stakeholders and the CDT students. The research will be structured around three theme areas: Biology of Disease, Molecule and Assay Design and Structural Biology and Computation. The CDT brings together leading researchers with a proven track record across these areas and who have pioneered recent advances in the field, such as multiple approved cancer treatments. Their combined expertise will provide supervision and mentorship to the student cohort who will work on projects that span these research themes and bring their contributions to bear on the medical problems in question. The student cohort approach will allow teams of researchers to work together on joint projects with common goals. Projects will be proposed between academics, industrial partners and students with priority given to those with industrial relevance. The programme of research and training across the disciplines will equip graduates of the CDT with an unprecedented background of knowledge and skills across the disciplines. The programme of research and training across the disciplines will be supplemented by training and hands-on experiences of entrepreneurship, responsible innovation and project management. Taken together this will make graduates of the CDT highly desirable to employers, equip them with the skills they need to envisage and implement future innovations in the area and allow them to become the leaders of tomorrow. A structured and highly experienced management group, consisting of a director, co-directors, theme leads and training coordinators will oversee the execution of the CDT with the full involvement of industry partners and students. This will ensure delivery of the cohort training programme and joint events as well as being accountable for the process of selection of projects and student recruitment. The management team has an established track record of delivery of research and training in the field across industry and academia as well as scientific leadership and network training coordination. The CDT will be delivered as a single, fully integrated programme between Newcastle and Durham Universities, bringing together highly complementary skills and backgrounds from the two institutions. The seamless delivery of the programme across the two institutions is enabled by their unique connectivity with efficient transport links and established regional networks. The concept and structure of the CDT has been developed in conjunction with the industrial partners across the pharmaceutical, biotech and contract research industries, who have given vital steer on the desirability and training need for a CDT in this area as well as to the nature of the theme areas and focus of research. EPSRC funding for the CDT will be supplemented by substantial contributions from both Universities with resources and studentship funding and from industry partners who will provide training, in kind contribution and placements as well as additional studentships.

Protein based drugs are revolutionising the precision treatment of cancer and other complex disease, and often consist of large macromolecules like antibody proteins, that can act when they are attached to a small molecule drug. An example of this new type of "biologic" medicine are antibody-drug conjugates (ADCs) which are leading the way in personalised chemotherapy treatments for cancer, with >100 such drugs in clinical trials or pharmaceutical pipeline all over the world. However, the bottleneck in progressing this field further is not the antibodies, or the drugs available, but the chemistry required to stitch these two components together, and developments in this area of chemistry lag decades behind other branches of small molecule organic chemistry. A major challenge in the construction of these medicines is the difficulty in building linkages between small molecules and proteins that are stable enough to survive in the body during circulation, but then also labile enough to break-down inside the targeted cancer cells, which is required for full activity. An ideal solution to this problem would be the development of a reversible linkage which is stable until exposed to an external small molecule trigger which would then catalyse break-down of the linkage. A reversible method such as this would also have a wide ranging cost-effective application in the in vitro purification of therapeutic proteins, including 'fishing' antibodies and other proteins out of complex mixtures before preparing them for clinical applications- akin to a 'catch-and-release' strategy. Nature makes abundant use of similar reversible modifications including glycosylation, phosphorylation, acetylation and lipidation, which all act as dynamic switches, as yet however our ability as chemists to emulate these enzymatic modifications pales in comparison. In this project we will take inspiration from Nature and address this limitation by developing a new chemical method which will allow the reversible attachment of small molecules to protein scaffolds. We ultimately aim to deploy this method, both in vitro and in vivo, for the tandem purification and modification of antibody fragments, and the subsequent controlled release of a drug inside bladder cancer cells- a disease which results in 15 deaths every day in the UK. To achieve this goal we will assemble a team with multidisciplinary expertise at the University of York, working at the interface of small molecule and protein chemistry, glycoscience, bladder cancer cell biology, and antibody production. We will also establish a collaborative relationship with a UK biotech specialising in the development of antibody-drug conjugates (ADCs). This unique combination will facilitate the development of a novel reversible protein bioconjugation platform method, which will be used to overcome the challenges presented in the production of these 21st century therapeutics.

Labelling of proteins is fundamental to laboratory investigations and industrial applications such as the development of diagnostics. The market for protein labelling reagents is worth approximately $2bn a year and new innovations which increase the efficiency of protein labelling and reduce the cost of this process are always needed. In this project, we are developing a new protocol for the use of sortase in protein labelling. This technology has the potential to allow the rapid (<1 hour) generation of homogenously modified proteins with minimal excess reagent and small quantities of the labelling protein. During the project we will investigate a range of potential commercial applications including the potential of the technology for application in the generation of modified antibodies, which represent a major new class of anti-cancer drugs.